Venous thromboembolic disease (VTE) typically involves life-threatening blood clots in legs and/or lungs and annually causes 500,000 hospitalizations and >50,000 deaths in the United States. The major goal of this innovative, high-risk, high-yield, multi-disciplinary project is to use for the first time "untargeted metabolomics" to analyze plasma from VTE cases and controls in order to discover novel plasma metabolite biomarkers for VTE risk. Untargeted metabolomics denotes the profiling of all low molecular weight biochemicals, including lipids, hormones, saccharides, nucleotides, organic acids, and amino acids that serve as substrates and products in metabolic pathways. Plasma low molecular weight biochemicals are measured without specific "targeting" of specific metabolites or analytes. Our preliminary studies show that several normal plasma lipid metabolites possess previously unrecognized anticoagulant and procoagulant activities. Thus, in hypothesis- driven research, we hypothesize that imbalances of known and unknown plasma lipid metabolites are associated with increased VTE risk. Furthermore, in hypothesis-generating research, we hypothesize that imbalances of certain plasma metabolites including lipids, vitamins, hormones, saccharides, amino acids, nucleotides, and/or organic acids are biomarkers for VTE risk. The Specific Aim of this project is to discover new plasma metabolite biomarkers associated with VTE risk using LC-MS/MS-based untargeted metabolomics studies that permit simultaneous measurements of approximately 3,500 plasma metabolites. This project draws on the complementary strengths of multiple Scripps investigators including two co-PIs, Dr. Griffin, a senior project manager with a strong track record in discovery of VTE risk factors and Dr. Deguchi, an experienced physician scientist with a strong track record in translational clinical research. Key personnel include a senior pioneer in mass spectrometry studies of untargeted metabolomics, Dr. Siuzdak, who heads the Scripps Center for Mass Spectrometry. Clinical samples from 522 VTE cases and 522 matched controls are available from two existing registries, permitting an immediate, intense exploration of the potential applicability of untargeted metabolomics for VTE biomarker research. If successful, this potentially high impact project could lead to clinical insights with significant clinical utility for patients at risk for VTE. 7. Public Health Relevance: Deep vein thrombosis and pulmonary embolism (VTE) in the USA annually result in 500,000 hospitalizations and >50,000 deaths. To understand VTE risk and to prevent or treat VTE, we need much more knowledge because approximately 30-50% of VTE patients have no known risk factors. To discover new biomarkers for risk of VTE, we will screen >3,500 metabolites normally found in blood plasma from approximately 1,000 VTE subjects using pioneering state-of-the-art mass spectrometry based technologies.